No abstract

Genetic studies in fruit flies have implicated the chromatin remodeling complex NURF in immunity, but it has yet to be studied in mammals. Here we show that its targeting in mice enhances antitumor immunity in two syngeneic models of cancer. NURF was disabled by silencing of BPTF, the largest and essential subunit of NURF. We found that both CD8+ and CD4+ T cells were necessary for enhanced antitumor activity, with elevated numbers of activated CD8+ T cells observed in BPTF-deficient tumors. Enhanced cytolytic activity was observed for CD8+ T cells cocultured with BPTF silenced cells. Similar effects were not produced with TCR transgenic CD8+ T cells, implicating the involvement of novel antigens. Accordingly, enhanced activity was observed for individual CD8+ T cell clones from mice bearing BPTF silenced tumors. Mechanistic investigations revealed that NURF directly regulated the expression of genes encoding immunoproteasome subunits Psmb8 and Psmb9 and the antigen transporter genes Tap1 and Tap2. The PSMB8 inhibitor ONX-0914 reversed the effects of BPTF ablation, consistent with a critical role for the immunoproteasome in improving tumor immunogenicity. Thus, NURF normally suppresses tumor antigenicity and its depletion improves antigen processing, CD8 T cell cytotoxicity and antitumor immunity, identifying NURF as a candidate therapeutic target to enhance antitumor immunity.

Purpose: To compare the performance of Kerasave (AL.CHI.MI.A. S.R.L., Ponte San Nicolò, Italy) containing 2.5 μg/mL of amphotericin B and Optisol-GS (Bausch & Lomb, Bridgewater, NJ) cold corneal storage media on donor corneas during routine eye bank procedures. Methods: Forty-four paired donor corneas were preserved after swab sample collection and povidone-iodine decontamination. Right and left corneas were immersed in Kerasave and Optisol-GS, respectively, and stored at 4°C before the initial evaluation. Paired corneas were assigned to processing subgroups for penetrating keratoplasty (n = 20), Descemet stripping automated endothelial keratoplasty (n = 14), or Descemet membrane endothelial keratoplasty (n = 10). Endothelial cell density, central corneal thickness, slit-lamp examination, and endothelial cell damage were assessed at different intervals. Sterility testing was performed on media samples. Results: At the initial evaluation, after 25.6 ± 3.2 hours of storage, the mean central corneal thickness of all corneas in Kerasave (n = 22) was greater than those in Optisol-GS (n = 22) (571 ± 12 μm vs. 526 ± 10 μm, respectively; P = 0.006). All other metrics were comparable between Kerasave and Optisol-GS in processing subgroups at all time intervals. Corneal swabs were positive in 90% of corneas before decontamination with povidone-iodine. At the initial evaluation, fungal contamination was detected in 24% and 19% of Kerasave and Optisol-GS, respectively. At the final evaluation, no fungi was detected in Kerasave and 1 Optisol-GS sample was positive (P = 0.999). Conclusions: Metrics of corneas stored in Kerasave and Optisol-GS were comparable. Kerasave might be considered an antifungal-possessing alternative to Optisol-GS.